Atherothrombosis which induces myocardial infarction, brain infarction, or the like and develops due to arteriosclerosis, and deep venous thrombosis which induces pulmonary embolism is are leading causes of human deaths. Warfarin, which is currently most used as an anticoagulant with the indication for the “treatment and prevention of thromboembolism (venous thrombosis, myocardial infarction, pulmonary embolism, brain embolism, slowly progressive cerebral thrombosis, etc.)”, exhibits an excellent antithrombotic effect, whereas this anticoagulant disadvantageously hinders arrest of bleeding and causes hemorrhagic complications as severe adverse reaction. Against this backdrop, there has been a strong demand for the development of therapeutic and prophylactic agents for thrombosis or thromboembolism having a novel mechanism of action that suppresses the growth of pathological thrombus and does not influence arrest of bleeding from vascular vessels.
Many blood coagulation factors (cascade) are known to participate in arrest of bleeding and thrombus formation. Accordingly, if a particular blood coagulation factor can be controlled by elucidating the mechanisms of action of individual blood coagulation factors, this may work as a promising approach to solve the problems described above. In recent years, factor XI (FXI), which is one of the intrinsic blood coagulation factors, has been found to be greatly involved in the growth of pathological thrombus (see Non Patent Literatures 1 and 2). Specifically, it has been revealed that the enhanced blood coagulation cascade that yields activated factor XI (FXIa) from FXI plays an important role in the course of growth of pathological thrombus. It has been further revealed that FXI is not involved in the mechanism underlying arrest of bleeding. In actuality, research using FXI-knockout mice has confirmed an antithrombogenic effect in venous thrombus models and demonstrated that this effect does not influence the time required for arrest of bleeding (see Non Patent Literature 3). Thus, the inhibition of the functions of FXIa (hereinafter, also referred to as FXIa inhibition) is a very attractive approach to solve the problems described above.
Patent Literature 1 discloses that a 3-substituted proline derivative represented by the following formula has excellent FXIa inhibition activity and is useful as a drug for treating thrombosis and thromboembolism:
wherein ring D represents a phenyl ring or a 5- or 6-membered heteroaryl ring; m represents 0, 1, or 2; Ra represents an optionally substituted 5- to 10-membered heteroaryl group or the like; a plurality of Rb moieties each independently represent a halogen atom or the like; L represents —CR61—CR71—, —CR61R62—CR71R72—, —NR61—C(═O)—, or —CR61R62—NR71— wherein R61, R62, R71, and R72 each independently represent a hydrogen atom or the like; Rc represents an optionally substituted C6-10 aryl group or the like; Rd represents a hydrogen atom or the like; and ring Q represents a group represented by formula (3a′) or the like.
Patent Literature 2 discloses that a pyrrolidine derivative represented by the following formula (I) has selective FXIa inhibition activity and is useful as a drug for treating thromboembolism:
wherein Cyc A represents C3-C8 cycloalkyl or the like; Cyc B represents C6-C10 aryl, 5- to 10-membered heteroaryl, or the like; Cyc C represents C3-C8 cycloalkyl or the like; R1 represents —C1-4 alkylene-NH2 or the like; t represents 0 to 6; R2 represents —COOH or the like; m represents 0 to 6; R3 represents —CO—NH2 or the like; n represents 0 to 6; R4 represents a single bond or the like; and R5 represents —CO—NH— or the like.